Protocolized reduction of non-resuscitation fluids versus usual care in septic shock patients (REDUSE): a randomized multicentre feasibility trial

Background/purpose Non-resuscitation fluids constitute the majority of fluid administered for septic shock patients in the intensive care unit (ICU). This multicentre, randomized, feasibility trial was conducted to test the hypothesis that a restrictive protocol targeting non-resuscitation fluids reduces the overall volume administered compared with usual care. Methods Adults with septic shock in six Swedish ICUs were randomized within 12 h of ICU admission to receive either protocolized reduction of non-resuscitation fluids or usual care. The primary outcome was the total volume of fluid administered within three days of inclusion. Results Median (IQR) total volume of fluid in the first three days, was 6008 ml (interquartile range [IQR] 3960–8123) in the restrictive fluid group (n = 44), and 9765 ml (IQR 6804–12,401) in the control group (n = 48); corresponding to a Hodges–Lehmann median difference of 3560 ml [95% confidence interval 1614–5302]; p < 0.001). Outcome data on all-cause mortality, days alive and free of mechanical ventilation and acute kidney injury or ischemic events in the ICU within 90 days of inclusion were recorded in 98/98 (100%), 95/98 (98%) and 95/98 (98%) of participants respectively. Cognition and health-related quality of life at six months were recorded in 39/52 (75%) and 41/52 (79%) of surviving participants, respectively. Ninety out of 134 patients (67%) of eligible patients were randomized, and 15/98 (15%) of the participants experienced at least one protocol violation. Conclusion Protocolized reduction of non-resuscitation fluids in patients with septic shock resulted in a large decrease in fluid administration compared with usual care. A trial using this design to test if reducing non-resuscitation fluids improves outcomes is feasible. Trial registration Clinicaltrials.gov, NCT05249088, 18 February 2022. https://clinicaltrials.gov/ct2/show/NCT05249088 Supplementary Information The online version contains supplementary material available at 10.1186/s13054-024-04952-w.

Steering group: Management group and principal site investigators as indicated above.

Investigator responsibilities
The trial steering group designed the trial.Principal site investigators vouch for the data recorded at each hospital.Data analysis was independently performed by two statisticians (Janus C Jakobsen and Markus H Olsen).A final statistical report was written after consensus was achieved.The steering group vouches for the accuracy and completeness of the data and analysis and for the adherence of this report to the trial protocol and the statistical analysis plan.The initial version of the manuscript was drafted by the first and last authors and was further developed and approved by all authors.The funders had no role in the analysis of the data, in the preparation or approval of the manuscript, or in the decision to submit the manuscript for publication.

Data collection and verification
Data for the baseline characteristics and primary and secondary outcome measures were obtained from hospital charts, except for the six-month follow up.Assessment of functional outcome at the sixmonth follow-up was made at a face-to-face follow-up or by telephone contact with patients or their relatives.The trial was externally monitored by national monitoring offices coordinated by the clinical trial manager and Clinical Studies Sweden, Forum South.All variables were collected in a patient-specific trial ledger or directly in an electronic case report form (eCRF) which was created in collaboration with Spiral Software (New Zealand).Site principal investigators were responsible for training of clinical staff on how to enter variables correctly.Special emphasis was placed on how to record fluid administration and fluid balance in a standardized manner.Instructions were available in the trial ledger and in the eCRF.All sites had a digital site initiation meeting with monitors before start of inclusion and an on-site meeting at end of study.The meetings included control of routines for data collection and data entry as well as quality control of data by comparing selected source data with data entered in eCRF.The principal site investigator was responsible for ensuring that all relevant data were entered into the eCRF.To promote data quality, the eCRF had several inbuilt mechanisms to prevent data entry errors such as range checks for data values.

Details of the intervention
Patients received non-resuscitation fluids according to their allocated treatment arm as soon as possible, at the latest within two hours of inclusion.Prior to initiation of the trial, site investigators established what constituted 'usual care' at their site, to limit drift in the usual care group.

Differences between the statistical report and the presented results
In the statistical report, the analysis of protocol deviations including the three participants that were randomized without fulfilling the inclusion criteria and immediately withdrawn was erroneously classified as a sensitivity analysis.This analysis should have been classified as the primary analysis and is presented as such.

Fluids
Fluid balance was calculated as sum of all input of enteral and parenteral fluids minus all measured losses.Estimated loss through evaporation was not included in fluid balance.Stool was not included in the fluid balance unless the patient had a faecal management system or similar device in place.Crystalloids were classified as resuscitation fluids if administered to correct hemodynamic impairment as noted in the patient chart or given at a rate > 5 ml/kg/h (Finfer 2010).

Complications
Complications were defined as follows: • acute kidney injury, according to the KDIGO criteria .In patients without data on creatinine prior to hospital admission, the baseline creatinine was estimated using the chronic kidney disease epidemiology (CKD-EPI) equation (Inker -21).
• ischemic events in the ICU (cerebral, cardiac, intestinal or limb ischemia) within 90 days of inclusion.Cerebral ischemia was defined as ischemia seen on magnetic resonance imaging (MRI) or computer tomography (CT) scan; cardiac ischemia as myocardial infarction/unstable angina AND treatment as a consequencepercutaneous coronary intervention (PCI)/thrombolysis or initiation/increased antithrombotic treatment; intestinal ischemia as diagnosed during surgery or by angiography; limb ischemia if in combination with treatmentopen/percutaneous vascular intervention, amputation, initiation of/increased antithrombotic treatment In addition to the patient-centred complications above, the following complications were registered: • Hypoglycaemia (≤ 3.9 mmol/l)

Protocol deviations
Protocol deviations include randomization of a non-eligible patient and non-compliance with the treatment algorithm in the intervention arm.

Frailty score
Frailty score refers to the first version, described by Rockwood et al .

Site of infection
The site of infection was characterized according to the Mellhammar-Linder criteria .

Statement on data sharing
Beginning nine months after publication of the main report of this trial individual de-identified data will be available for sharing with researchers who provide a methodologically sound proposal as judged by the steering committee.To gain access, data requestors will need to sign a data access agreement.Proposals should be directed to the principal investigator via email: peter.bentzer@med.lu.se and will be reviewed by the REDUSE-trial steering group.

SENSITIVITY ANALYSES
The generalized estimating equation resulted in a difference of 945 (95% CI 556-1335 p<0.001) ml between the restrictive fluid group and usual care group.The results of the other sensitivity analyses are shown below, in Table S2.

TABLES
Table S1.Total fluid administered in the first three days (D0-D3) presented in various time frames.Data for the restrictive fluid group and usual care are presented as the median (interquartile range).Differences are presented as median differences with 95% Hodge Lehmann (HL) confidence intervals (CI).Complete case analysis: included patients still admitted on the third ICU day (D0-3).Per-protocol: including only patients whom fulfilled the inclusion criteria and received the intervention.e) Starting at 72 hours after randomization, glucose solutions may be prescribed at a maximum dose of 1g/kg/day, if enteral nutrition is not tolerated.Glucose solutions, at this dose or lower, may be started earlier than day 4 in patients with insulin dependent diabetes, if enteral nutrition is not tolerated and if local protocol demands it.The minimum concentration must be 20% unless the patient is dehydrated.f) Diuretics can be prescribed to reach the desired fluid balance.
Volume of non-resuscitation fluids administered the first three days(D0-D3), according to treatment group.presented as median (interquartile range).
• Electrolyte and metabolic disturbances (hypernatremia > 159 mmol/L, hyperchloremic acidosis [pH < 7.15 and plasma Cl -> 115], metabolic alkalosis [pH > 7.59 and standard base excess (S-BE) > 9]) • Suspected unexpected serious adverse complication (SUSAC) -an adverse event not reasonably explained by factors other than the intervention which may cause death, or be life threatening, prolong hospitalisation, or may result in significant disability/incapacity.

Table S3 . Cumulative total volume administration -all available data
Data presented as median (interquartile range).D: Day.* corresponds to Day 1-5 in the CLASSIC trial and in our previous observational trial (Lindén-Søndersø et al. 2019).

Table S5 . Secondary exploratory clinical outcome.
Data are presented as the median (interquartile range) or number (%), as appropriate.KDIGO -Kidney Disease Improving Global Outcome, RRTrenal replacement therapy, SOFA -Sequential Organ Failure Assessment, GOSE -Glasgow Outcome Scale Extended.§Number of patients: 44 (restrictive fluid group) and 48 (usual care).¤Number of patients: 45 (restrictive fluid group) and 48 (usual care).*Definedas no need for intravenous nutrition or fluids.¶Number of patients: 22 (restrictive fluid group) and 21 (usual care).Differences in count outcomes are presented as median differences with 95% Hodge Lehmann (HL) confidence intervals (CI).All available data was used for all fluid calculations, i.e. fluid data includes data from patients staying less than three days.

Table S7 . Post hoc-analyses of exploratory outcomes.
¤One patient was transferred to a non-study ICU.

Table S8 . Acute kidney injury stage within 90 days
Acute kidney injury, according to KDIGO (Kidney Disease Improving Global Outcome).One patient in the restrictive fluid group and one in usual care was relocated to a non-study ICU.The χ 2 -test was used for the statistical analysis.